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Breast Cancer Research
Published in: Breast Cancer Research 1/2016

Open Access 01-12-2016 | Research article

Patient survival and tumor characteristics associated with CHEK2:p.I157T – findings from the Breast Cancer Association Consortium

Authors: Taru A. Muranen, Carl Blomqvist, Thilo Dörk, Anna Jakubowska, Päivi Heikkilä, Rainer Fagerholm, Dario Greco, Kristiina Aittomäki, Stig E. Bojesen, Mitul Shah, Alison M. Dunning, Valerie Rhenius, Per Hall, Kamila Czene, Judith S. Brand, Hatef Darabi, Jenny Chang-Claude, Anja Rudolph, Børge G. Nordestgaard, Fergus J. Couch, Steven N. Hart, Jonine Figueroa, Montserrat García-Closas, Peter A. Fasching, Matthias W. Beckmann, Jingmei Li, Jianjun Liu, Irene L. Andrulis, Robert Winqvist, Katri Pylkäs, Arto Mannermaa, Vesa Kataja, Annika Lindblom, Sara Margolin, Jan Lubinski, Natalia Dubrowinskaja, Manjeet K. Bolla, Joe Dennis, Kyriaki Michailidou, Qin Wang, Douglas F. Easton, Paul D. P. Pharoah, Marjanka K. Schmidt, Heli Nevanlinna

Published in: Breast Cancer Research | Issue 1/2016

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Abstract

Background

P.I157T is a CHEK2 missense mutation associated with a modest increase in breast cancer risk. Previously, another CHEK2 mutation, the protein truncating c.1100delC has been associated with poor prognosis of breast cancer patients. Here, we have investigated patient survival and characteristics of breast tumors of germ line p.I157T carriers.

Methods

We included in the analyses 26,801 European female breast cancer patients from 15 studies participating in the Breast Cancer Association Consortium. We analyzed the association between p.I157T and the clinico-pathological breast cancer characteristics by comparing the p.I157T carrier tumors to non-carrier and c.1100delC carrier tumors. Similarly, we investigated the p.I157T associated risk of early death, breast cancer-associated death, distant metastasis, locoregional relapse and second breast cancer using Cox proportional hazards models.
Additionally, we explored the p.I157T-associated genomic gene expression profile using data from breast tumors of 183 Finnish female breast cancer patients (ten p.I157T carriers) (GEO: GSE24450). Differential gene expression analysis was performed using a moderated t test. Functional enrichment was investigated using the DAVID functional annotation tool and gene set enrichment analysis (GSEA). The tumors were classified into molecular subtypes according to the St Gallen 2013 criteria and the PAM50 gene expression signature.

Results

P.I157T was not associated with increased risk of early death, breast cancer-associated death or distant metastasis relapse, and there was a significant difference in prognosis associated with the two CHEK2 mutations, p.I157T and c.1100delC. Furthermore, p.I157T was associated with lobular histological type and clinico-pathological markers of good prognosis, such as ER and PR expression, low TP53 expression and low grade. Gene expression analysis suggested luminal A to be the most common subtype for p.I157T carriers and CDH1 (cadherin 1) target genes to be significantly enriched among genes, whose expression differed between p.I157T and non-carrier tumors.

Conclusions

Our analyses suggest that there are fundamental differences in breast tumors of CHEK2:p.I157T and c.1100delC carriers. The poor prognosis associated with c.1100delC cannot be generalized to other CHEK2 mutations.
Appendix
Available only for authorised users
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Metadata
Title
Patient survival and tumor characteristics associated with CHEK2:p.I157T – findings from the Breast Cancer Association Consortium
Authors
Taru A. Muranen
Carl Blomqvist
Thilo Dörk
Anna Jakubowska
Päivi Heikkilä
Rainer Fagerholm
Dario Greco
Kristiina Aittomäki
Stig E. Bojesen
Mitul Shah
Alison M. Dunning
Valerie Rhenius
Per Hall
Kamila Czene
Judith S. Brand
Hatef Darabi
Jenny Chang-Claude
Anja Rudolph
Børge G. Nordestgaard
Fergus J. Couch
Steven N. Hart
Jonine Figueroa
Montserrat García-Closas
Peter A. Fasching
Matthias W. Beckmann
Jingmei Li
Jianjun Liu
Irene L. Andrulis
Robert Winqvist
Katri Pylkäs
Arto Mannermaa
Vesa Kataja
Annika Lindblom
Sara Margolin
Jan Lubinski
Natalia Dubrowinskaja
Manjeet K. Bolla
Joe Dennis
Kyriaki Michailidou
Qin Wang
Douglas F. Easton
Paul D. P. Pharoah
Marjanka K. Schmidt
Heli Nevanlinna
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2016
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-016-0758-5

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